Over the last four years we made substantial contributions to the world literature in providing the first descriptions of specific, rare and most severe chronic GVHD manifestations or medical complications. The studies of biology included peripheral blood and target tissues research biopsies (skin, oral mucosa) which is a unique characteristics of this program. This study protocol enrolled more than 400 well characterized chronic GVHD patients with 90% of them referred from across the US and some internationally (Europe). The current cross-sectional natural history study of chronic GVHD will continue to be a continuous source of publications and a backbone of the NIH chronic GVHD study group over the next four years In a collaborative effort with Dr. Fran Hakim (ETIB PDCM) we have proposed a new model of chronic GVHD pathogenesis, whereby interferon (IFN)-mediated processes drive expansion and differentiation of T-effectors and their emigration into tissues. In collaboration with colleagues from the NIDCR laboratory (Dr. Jackie Mays) we conducted a pilot study of the salivary proteomics profile in chronic GVHD to identify disease biomarkers and study the salivary environment and biopsies in the larger cohort of chronic GVHD patients. Future studies will focus on the utilization of high sensitivity assays to develop chronic GVHD cytokine biomarkers (Dr. Cao Liang, CCR) and the genomic techniques (Dr. Daoud Meerzaman, NCI) to determine the biological patterns and clinical phenotypes using the natural history study patient samples. We recently completed accrual to three in-house prospective randomized phase 2 therapy studies and the date are being analyzed: a) prevention of chronic GVHD (unrelated donor transplant protocol of alemtuzumab vs. no lymphodepletion), b) treatment of steroid refractory chronic GVHD with pomalidomide, and c) treatment of refractory oral chronic GVHD (clobetasol rinses). The key goal of this program is to develop new and safer molecularly targeted therapies which will allow us to depart from current toxic drugs such as steroids or calcineurin inhibitors and allow more specific interference in the disease process and to develop better salvage treatments. This approach will also allow entry of new pharmacological immunomodulators in the clinical allogeneic transplantation in general by defining initial safety, PK, PD and dosing properties. Two new phase 2 investigator initiated studies are IRB approved and started enrolling patients - ponesimod S1P1 inhibitor (Actelion CRADA) and AZD 9668 neutrophil elastase inhibitor for lung chronic GVHD (Astra Zeneca/NCATS CTA. The Actelion study is also aiming for FDA regulatory approval. We are currently opening a phase 1-2 study of baricitinib a JAK 1/2 inhibitor (Lilly CRADA) and pacritinib (CTI); the latter is planned as a multicenter study coordinated by our group. The front line pilot targeting B-cell and T-cell signaling pathways by ibrutinib before steroids is in the process of planning. We also just opened the palifermin (KGF) chronic GVHD prevention phase 1-2 dose escalation study in unrelated donors as a collaborative effort with the Dr. Ronald Gress laboratory. The original 2005 NIH chronic GVHD consensus conference spearheaded by this intramural program resulted in six seminal papers which have been referenced more than 2200 times in the peer reviewed literature which places them among most referenced papers in the BMT field. All six new working group publications of the 2014 consensus have been already published in the Biology of Blood and Marrow Transplantation, the official journal of the American Society for Blood and Marrow Transplantation, between December 2014 and May 2015. The specific aim #3 is largely utilizing and validating the tools and recommendations proposed by the 2014 NIH chronic GVHD consensus. Our contributions to national and international collaborations and initiatives in chronic GVHD will continue.